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42156-G1
Catalytic Enantioselective Disilylations of Electron Deficient Alkenes Promoted by Lewis Bases
The original proposed research for this grant entailed the development of catalytic disilylations of activated alkenes. With significant preliminary results, we embarked on this research and managed to obtain moderate levels of enantioselectivity for this reaction. Due to the loss of personnel on this project in 2004, an executive decision was made to change focus while still developing organosilane methodology. The underlying interest from the proposed project, mainly the combination of Lewis bases and silicon-containing molecules, has opened new directions in our research program. During the grant period, we employed thiazolium carbinols as preformed acyl anions. The support from the PRF facilitated our early studies in these thiazolium carbinols and the studies of acylsilanes with Lewis bases. With PRF support, we have developed:
• The direct nucleophilic acylation of nitroalkenes
• The addition of carbonyl anions to o-quinone methides, and
• A general solution to the cross-acyloin reaction.
Reactions that utilize polarity reversal, or Umpolung, strategies enable the development of new methods to construct compounds with important biological properties. Acyl anions are one useful class of reactive intermediates that can be generated from the polarity reversal of carbonyl functionalities. Initial investigations conducted in our laboratory in 2005 and 2006 revealed that N-heterocyclic carbenes (NHCs), derived from thiazolium salts and DBU (1,8-diazobicyclo[5.4.0]undec-7-ene), can be utilized to catalyze the generation of acyl anion equivalents from acylsilanes. While examining this process, we became interested in better understanding the pathway of the catalytic cycle. An early mechanistic study involved the preparation of an O-silyl protected thiazolium carbinol, a proposed intermediate in the reaction pathway. We were pleased to find all experiments provided evidence that the carbinol is an intermediate in the reaction and we were able to conclude that protected thiazolium carbinols are operative acyl anion precursors.
Once we established that protected thiazolium carbinols are suitable acyl anion precursors, we investigated their utility over the last 2 years. While our previous studies found amine bases promote the addition of carbinols to imines and chalcone, we were curious if fluoride could also be used to access the carbonyl anion reactivity. The examination of these novel acyl anion precursors began by combining thiazolium carbinol with nitroalkene and a fluoride source. Direct nucleophilic acylations of nitroalkenes has not been reported in the literature until our PRF-supported work. This is most likely because bases used to generate carbonyl anions cause the nitroalkene to decompose. Gratifyingly, the desired bond-forming event can be achieved using this fluoride strategy and the corresponding ?-nitroketones are obtained in good yield. The optimization of reaction conditions revealed that activation of the nitroalkene with a thiourea was necessary to obtain high yields and tetramethylammonium fluoride was the highest yielding fluoride source. This reaction can be rendered asymmetric (74% ee) when chiral thioureas derived from cinchona alkaloids are employed as additives in this transformation.
In the interest of further developing the utility of protected thiazolium carbinols as acyl anion precursors, we became curious if o-quinone methide species would also be operative electrophiles. We were pleased to find treatment of silyl-protected phenols and thiazolium carbinols with tetramethylammonium fluoride (TMAF) provided direct access to the ?-aryl ketone products in good yield (60-75%). Furthermore, the ?-aryl ketones produced can be easily converted to the corresponding benzofurans upon simple addition of acid. This methodology has been applied to a short synthesis of demethylmoracin I, a naturally occurring aromatase inhibitor. The direct synthesis of benzofurans has important applications since this particular class of molecule is found in approximately 200 natural products and 340 compounds with pharmacological activity (according to the Beilstein database).
Lastly, the use of fluoride instead of base to access carbonyl anions has allowed us to develop cross-acyloin reactions in good yields between thiazolium carbinols and aldehydes. This work is the first general Umpolung approach to ?-hydroxy ketones that does not require unmasking the carbonyl group after the key carbon-carbon bond has been formed.
Future applications of these “acyl anions in a bottle” will include the development of new bond forming reactions such as alkylations, additions to imines and conjugate additions. Ultimately, our interest in combining Lewis bases with silicon-containing molecules should lead to more useful chemical methodology for the synthesis of target molecules. The support of the PRF in the form of a Type G grant facilitated the exploration of unique and versatile thiazolium carbinols as carbonyl anion equivalents.
